Bronchogenic carcinoma: immunologic aspects.

Evidence that host immunologic function may influence the behavior of lung cancer is accumulating. Non-small-cell lung cancers are heavily infiltrated by host lymphocytes. The fact that monoclonal antibodies have been developed against lung cancer cells implies that such cells express surface antigens and are therefore vulnerable to immune recognition. Failure of the host defense mechanism to control tumor growth may involve (1) reduced natural killer cell activity, (2) inadequate lymphokine-activated killer cell function, or (3) tumor secretion of immunomodulating factors. Basic immunologic research studies of lung cancer are increasing the potential for clinical applications. New monoclonal antibodies have improved both the sensitivity and the specificity of immunohistopathologic analyses of pulmonary specimens. Links between immune function and prognosis in patients with lung cancer have been established. Finally, initial results from protocols that have used tumor-infiltrating lymphocytes, interleukin 2, and tumor vaccines suggest that immunobiologic treatment modalities may be increasingly applicable in patients with lung cancer.

Lung disease associated with orally administered mesalamine for ulcerative colitis.

Pulmonary symptoms, bilateral interstitial infiltrates and gas exchange abnormalities developed in a patient with ulcerative colitis treated with orally administered mesalamine. Improvement of symptoms and objective findings occurred after drug discontinuation. To the best of our knowledge, this is the first report of lung toxicity associated with orally administered mesalamine.

Clinical utility of bronchoalveolar lavage in immunocompromised hosts.

Bronchoalveolar lavage (BAL) has been used extensively for assessment of immunocompromised hosts with pulmonary infiltrates. Reported estimates of the diagnostic utility of BAL have varied because of differences in patient populations, diagnostic criteria, and study methods. Herein we report on the use of BAL to determine at least one of the final diagnoses in 150 immunocompromised patients. Although the frequency with which BAL provided at least one of the final diagnoses (overall diagnostic yield) was seemingly low (39%), the yield increased substantially when only patients with pathologically proven diagnoses were considered. The sensitivity of BAL was 82%, and the specificity was 53%. The use of rigid diagnostic criteria enabled us to distinguish pathogens from colonizers. Pneumocystis was considered a pathogen whenever it was identified. It was the most common infectious pathogen identified (50%) despite the fact that our study population had relatively few patients (only 4%) with acquired immunodeficiency syndrome (AIDS). Organisms such as cytomegalovirus, Aspergillus, and Candida were frequently identified in BAL specimens but were eventually proved to be pathogens in only 24%, 25%, and 0% of cases, respectively. BAL detected pulmonary malignant lesions on the basis of positive cytologic results in four of six patients eventually found to have primary or metastatic lung cancer. Our results should enhance the understanding of the strengths and weaknesses of BAL and assist in the interpretation of associated microbiologic findings.

Desmoplastic malignant mesothelioma masquerading as sclerosing mediastinitis: a diagnostic dilemma.

A 48-year-old woman presented with dyspnea, chest discomfort, and left vocal cord paralysis that developed 2 months after a flu-like illness. Radiographic examination showed prominence of mediastinal soft tissues and an ill-defined left upper lobe infiltrate. Dense mediastinal sclerosis was found at thoracotomy, and biopsy samples taken from the sclerotic areas showed densely hyalinized fibrotic tissue. Necrotizing granulomas containing organisms resembling Histoplasma capsulatum were present within mediastinal lymph nodes. Based on these findings, a diagnosis of sclerosing mediastinitis was made. During the next year, the patient's respiratory function deteriorated, and biopsy samples taken during a second thoracotomy 1 year later were again interpreted as sclerosing mediastinitis. The patient died postoperatively; at autopsy, the sclerotic mass involving the mediastinum was composed of a mixture of dense fibrosis and sarcomatous tissue. The final diagnosis was localized mediastinal desmoplastic malignant mesothelioma. We report it here because of its unusual clinical presentation, which mimicked sclerosing mediastinitis.

POEMS syndrome with idiopathic flushing mimicking carcinoid syndrome.

POEMS syndrome, a rare multisystem disease, is a variant of osteosclerotic myeloma and is characterized by polyneuropathy, organomegaly, endocrinopathy, monoclonal proteins, and skin changes. Presented herein is a case of POEMS syndrome with flushing. The flushing was intermittent, involving the face and upper third of the trunk, and was associated with hypotension and bronchospasm. Final diagnosis was made by biopsy examination of an axillary lymph node, which showed angiofollicular hyperplasia that stained strongly and selectively for lambda light chains. The patient had most of the typical features of POEMS syndrome but was unique in that her most striking finding was carcinoid-like flushing. The flushing improved with steroid therapy, as did some of the other clinical features of her disease. This case suggests that idiopathic flushing can be added to the skin changes observed in POEMS syndrome.

Bilious pleural effusion following liver biopsy.

Pleural effusions in patients with chronic liver disease are common and usually are of little consequence. Bilious pleural effusion can occur following percutaneous biopsy or cholangiography procedures if the pleura is traversed. This report emphasizes the role of biliary tract obstruction in the development of a bilious effusion and the importance of biliary tract decompression in treatment. We discuss the laboratory evidence supporting the diagnosis of bilious effusion and review the reported experience with this complication.

Evaluation of calcofluor white stain for detection of Pneumocystis carinii.

A rapid calcofluor white (CFW) stain for detecting Pneumocystis carinii was evaluated prospectively. Eighty-nine bronchoalveolar lavage (BAL) specimens, 21 open-lung biopsy (OLB) tissues, 2 induced sputums, 1 expectorated sputum, 2 tracheal secretions, and 1 bronchial secretion from 102 patients were examined for P. carinii cysts by both the CFW stain and a modified methenamine silver (MS) stain. Twenty episodes of P. carinii pneumonia were detected: 19 of these episodes were detected by CFW stain, and 16 of those episodes were detected by MS stain. Discrepancies between the two staining methods were resolved by review of the clinical histories and, in one case, by testing an OLB specimen. Neither staining procedure gave false-positive results with any specimen. More cysts were detected in CFW-stained specimens than in MS-stained specimens (p = 0.05). CFW stain is a simple, rapid, and inexpensive method for detecting P. carinii in clinical specimens and is at least as sensitive as MS stain.

Confirmation of lymphomatous pulmonary involvement by immunophenotypic and gene rearrangement analysis of bronchoalveolar lavage fluid.

Pathologic diagnosis of pulmonary involvement with lymphoma has traditionally necessitated open-lung biopsy in most cases. Specimens large enough to allow recognition of characteristic cytologic and architectural changes are usually not obtained bronchoscopically. Even when adequate biopsy specimens are available, however, unequivocal differentiation of lymphoma from benign inflammatory proliferative lesions (for example, pseudolymphoma or lymphocytic interstitial pneumonitis) is not possible on the basis of light microscopic findings alone. Pathologists have relied on immunohistologic examinations in which antibodies directed against B-cell and T-cell surface antigens are used to help distinguish benign from malignant lymphoid proliferations. Unfortunately, even immunohistologic findings may be nondiagnostic, particularly in T-cell lymphomas and in cases in which lymphoma is surrounded by a benign reactive lymphocytosis. Recent development of molecular biologic techniques (for example, Southern blotting) has provided the ability to detect a monoclonal population of cells based on detection of rearrangements of the genes that encode either B-cell immunoglobulin proteins or T-cell antigen receptor proteins. This technique is capable of detecting a clone of cells even when they constitute as little as 5% of a lymphoid infiltrate. Bronchoalveolar lavage can provide samples of sufficient size to facilitate Southern blotting. We present the first case wherein pulmonary involvement with a B-cell lymphoma was confirmed by both immunohistologic and molecular biologic studies of bronchoalveolar lavage fluid.

A prospective pilot study evaluating the effectiveness of secretory IgA measurements in bronchoalveolar lavage to detect non-small cell lung cancer.

Previous studies have described significant elevations in the concentrations of secretory immunoglobulin A (sIgA) in bronchial washings obtained from cancerous lungs. To date, there have been no prospective investigations examining the predictive value of sIgA measurements in clinically relevant settings. Our goal was to determine if measurement of sIgA in bronchoalveolar lavage (BAL) at the time of bronchoscopic evaluation of potentially malignant lung nodules might prospectively predict the presence of cancer. We observed no significant increase in the sIgA obtained from eight BALs obtained from cancerous lungs as compared with BALs taken from these same patients' contralateral cancer-free lungs. We also saw no significant difference in BAL (sIgA) obtained from patients eventually found to have cancer (N = 8) as compared with those found to have noncancer diagnoses (N = 6). In light of these findings, we think it unlikely that measurement of sIgA will be clinically useful in the diagnosis of pulmonary malignant neoplasms.

Clinical implications of the histopathologic diagnosis of pulmonary lymphomatoid granulomatosis.

We reviewed the epidemiologic, laboratory, roentgenographic, pulmonary function, and survival data from 28 patients who had a histologic diagnosis of lymphomatoid granulomatosis (LG) with involvement of the lungs. The mean age at the time of diagnosis was 51 years, and the male-to-female ratio was 3:2. Ten patients had other underlying diseases before LG was diagnosed. The most prominent symptoms were cough, dyspnea, fever, and rash, which were usually present for several months before diagnosis of LG. Multiple nodules were detected on a chest roentgenogram in 68% of the patients. Immunoglobulin concentrations were abnormal in 8 of 12 patients studied. Although bronchoscopy established the diagnosis in approximately a third of the patients who underwent this procedure, open-lung biopsy was uniformly diagnostic. The median survival was 72 months, with follow-up through 12 years. In 11 patients, the original diagnosis of LG was eventually changed to lymphoma. In five of these patients, the change in diagnosis was based on immunohistologic data obtained shortly after LG was discovered. Lymphoma diagnosed in this way was associated with a better prognosis than lymphoma diagnosed on the basis of conventional histopathologic findings. In three patients, solid tumors eventually developed. The diversity of clinical outcomes and frequent revisions of the diagnosis led us to consider the possibility that LG may also represent a histopathologic finding that occurs transiently in several disease processes.

Lymphokine-activated killer (LAK) cell activity in tumor-infiltrating lymphocytes from non-small cell lung cancer.

Tumor-infiltrating lymphocytes (TILs) are often seen in non-small cell lung cancers (NSCCs). Their functional role in the pathogenesis of lung cancer is unknown. The authors studied TILs in 27 patients with NSCC and determined the following: (1) the immunologic phenotype as defined by monoclonal antibodies against various surface markers, (2) activation state as indicated by interleukin-2 (IL-2) receptor expression and the kinetics of proliferation response to IL-2, and (3) the ability to develop lymphokine-activated killer (LAK) type cytotoxicity against both natural killer (NK)-resistant tumor cell targets (M14) and fresh autologous tumor cells. The authors' results show TILs from NSCCs to be a heterogeneous population composed of T-cells, B-cells, monocytes, and NK cells in frequencies similar to those found in peripheral blood lymphocytes (PBLs). TILs demonstrated increased IL-2 receptor expression and a more rapid proliferative response to IL-2 than PBLs, implying activation of TILs by the tumor milieu. Finally, TILs generated cytotoxicity against NK-sensitive (K562) and NK-resistant (M14) cell line targets consistently after in vitro treatment with IL-2 but were less consistent in their ability to lyse fresh autologous tumor cells and less effective than PBL LAK cells in lysing all targets. Comparison with LAK cells generated from normal volunteers suggests that decreased killing of autologous tumor cells only partially results from an inherent resistance to lysis by fresh NSCC targets. It appears, therefore, that tumor cells taken from NSCCs are not readily killed by the immune cells that infiltrate the tumor stroma and that this failure does not result from nonspecific immune deficiency in TILs.

Pulmonary edema associated with tocolytic therapy.

PURPOSE: To familiarize the general internist with the unique features of pulmonary edema occurring in association with tocolytic therapy (drugs used to inhibit uterine contractions). DATA IDENTIFICATION: The literature in English was searched using MEDLINE (1.966 to 1988), and bibliographies of pertinent articles and texts were reviewed. STUDY SELECTION: Fifty-eight case reports were examined by both authors and served as the database. DATA EXTRACTION: Several clinical variables, when available, were extracted from each case reported. Each variable was analyzed to provide an accurate composite description of pulmonary edema resulting from tocolytic therapy. RESULTS OF DATA SYNTHESIS: Patients with this syndrome present with dyspnea and may or may not have chest pain. Women at risk are receiving or have recently received sympathomimetic agents to arrest uterine contractions, with or without steroids. The incidence of the syndrome is higher in women with twin gestations. In postpartum cases, the syndrome usually occurs within 12 hours of delivery. Most women have intact membranes at presentation. Patients rarely have hypotension but usually have tachycardia and tachypnea. Chest roentgenograms usually show bilateral alveolar infiltrates and a normal-sized heart. Arterial blood gas values reveal an increased alveolar-arterial oxygen gradient. Hemodilution may cause a decrease in potassium values and the hematocrit. Patients respond rapidly to treatment with diuresis and oxygen administration and show clinical improvement usually within 24 hours. The underlying mechanism appears to be related to increased hydrostatic pressure and not to increased permeability or a direct toxic effect of tocolytic agents. CONCLUSIONS: Familiarity with the clinical features outlined above should increase the internist's ability to manage this problem without further invasive or noninvasive testing that might otherwise be used in evaluating dyspnea in pregnancy.

Cancer immunotherapy: current status of treatment with interleukin 2 and lymphokine-activated killer cells.

In recent years, the medical community has witnessed a growing interest in the use of adoptive immunotherapy in patients with malignant lesions refractory to standard treatments. Systemic administration of interleukin 2, in combination with the adoptive transfer of a patient's own activated immune cells, has resulted in objective regression of several types of advanced cancers. Pronounced regression of tumor has also been observed with use of systemic interleukin 2 alone. This ability to augment the immune defense system of the host against cancer has stimulated intense clinical and laboratory investigations.

In vitro activation of lymphocytes from nonsmall cell cancer patients by interleukin 2 and anti-CD3 antibody.

The current interest in adoptive immunotherapy of cancer has stimulated research into novel approaches of activating lymphocytes in vitro. We have studied the effect of anti-CD3 antibody on the in vitro activation of peripheral blood lymphocytes and tumor infiltrating lymphocytes (TIL) taken from patients with nonsmall cell cancer of the lung (NSCC). We demonstrate that anti-CD3 substantially enhances the proliferative response and bulk culture growth of interleukin 2 (IL-2)-activated killer cells. The addition of anti-CD3 to IL-2-treated TIL enhances their cytotoxicity against fresh autologous NSCC tumor targets, but not against the cancer cell lines K562 and M14. The effectors generated by culture in IL-2 and anti-CD3 have greatly increased IL-2 receptor expression and are predominantly CD4+ cells. These results establish anti-CD3 as a potentially powerful agent in the in vitro activation of lymphocytes from cancer patients.

Malignant mesothelioma of the pleura.

Malignant mesothelioma of the pleura most commonly occurs in persons with a heavy occupational exposure to asbestos. Some patients, however, have no such history of exposure. Clinical features include initial complaints of nonpleuritic chest pain and dyspnea. The most frequent roentgenographic finding is a unilateral pleural effusion. Thrombocytosis and elevated erythrocyte sedimentation rates are common. Pleural effusions are typically exudates, are often hemorrhagic, and are usually insufficient for diagnosing mesothelioma based on cytology alone. Even pleural biopsy may not produce enough tissue to enable the pathologist to make a firm diagnosis. Thoracotomy and open biopsy will confirm the diagnosis in most cases. Pathologic distinction from metastatic adenocarcinoma may be difficult even after the use of special stains and electron microscopy. Clinical deterioration is primarily attributable to local spread of tumor. Several factors seem to predict prolonged survival: (1) epithelial histologic subtype, (2) performance score, (3) age of the patient at the time of diagnosis, and (4) absence of chest pain. Surgical treatment, chemotherapy, and irradiation, alone or in combination, have been used for malignant mesothelioma. Except for the palliative effect of irradiation, most treatment protocols have not altered the dismal median survival of approximately 11 months seen in untreated patients with malignant mesothelioma.